Byoung Chul Cho1, Grace K Dy2, Ramaswamy Govindan3, Dong-Wan Kim4, Nathan A Pennell5, Gerard Zalcman6, Benjamin Besse7, Joo-Hang Kim8, Goekben Koca9, Prabhu Rajagopalan10, Simon Langer11, Matthias Ocker12, Hendrik Nogai13, Fabrice Barlesi14. 1. Yonsei Cancer Center, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. Electronic address: cbc1971@yuhs.ac. 2. Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA. Electronic address: grace.dy@roswellpark.org. 3. Washington University in St. Louis, 1 Brookings Dr, St. Louis, MO 63130, USA. Electronic address: rgovindan@wustl.edu. 4. Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul 03080, Korea. Electronic address: kimdw@snu.ac.kr. 5. Cleveland Clinic Taussig Cancer Institute, 10201 Carnegie Ave, Cleveland, OH 4419, USA. Electronic address: penneln@ccf.org. 6. University Hospital, Clinical Research Center, Avenue de la Côte de Nacre, 14033 Caen, France. Electronic address: zalcman-g@chu-caen.fr. 7. Gustave Roussy, 114 Rue Edouard Vaillant, 94800 Villejuif, France. Electronic address: benjamin.besse@gustaveroussy.fr. 8. CHA Bundang Medical Center, CHA University, 222 Yatap-dong, Bundang-gu, Seongnam-shi, Gyeongghi-do, Korea. Electronic address: kim123@cha.ac.kr. 9. Bayer AG, Müllerstraße 178, 13353 Berlin, Germany. Electronic address: goekben.koca@bayer.com. 10. Bayer HealthCare Pharmaceuticals, Inc., 100 Bayer Boulevard, PO Box 915, Whippany, NJ 07981, USA. Electronic address: prabhu.rajagopalan@bayer.com. 11. Chrestos Concept GmbH & Co. KG, Girardetstraße 1-5, 45131 Essen, Germany. Electronic address: simon.langer.ext@bayer.com. 12. Bayer AG, Müllerstraße 178, 13353 Berlin, Germany. Electronic address: matthias.ocker@bayer.com. 13. Bayer AG, Müllerstraße 178, 13353 Berlin, Germany. Electronic address: hendrik.nogai@bayer.com. 14. Aix Marseille University, Jardin du Pharo, 58, bd Charles Livon, 13284 Marseille, France; Assistance Publique Hôpitaux de Marseille, 80, rue Brochier, 13005 Marseille, France; Centre d'Essais Précoces en Cancérologie de Marseille (CLIP(2)), Hôpital La Timone - Basement F, 1st Floor, 264, rue St Pierre, 13885 Marseille, France. Electronic address: fabrice.barlesi@ap-hm.fr.
Abstract
OBJECTIVES: This phase Ib/II study evaluated safety, pharmacokinetics, maximum tolerated dose (MTD), and efficacy of the pan-cyclin-dependent kinase inhibitor roniciclib with cisplatin-etoposide (CIS-ETOP) or carboplatin-etoposide (CARBO-ETOP) in patients with extensive-disease small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS: In this open-label, non-randomized study, patients with previously untreated ED-SCLC received roniciclib twice daily (BID) in a 3 days on/4 days off schedule. Cisplatin 75 mg/m2 or carboplatin (AUC5) dose was administered on day 1, and etoposide 100 mg/m2 on days 1-3, of 21-day cycles. Phase Ib used a dose-escalation design to define the MTD for phase II. Pharmacokinetics were assessed. RESULTS: Forty-three patients received treatment (roniciclib 2.5 mg BID [+ CARBO-ETOP, n = 4; + CIS-ETOP, n = 3] and roniciclib 5 mg BID [+ CARBO-ETOP, n = 24; + CIS-ETOP, n = 12]). The MTD of roniciclib was 5 mg BID with CARBO-ETOP or CIS-ETOP. Common adverse events were nausea (90.7%) and vomiting (69.8%). Roniciclib was readily absorbed following oral administration at the MTD (median tmax 0.5-1 h), with a 30-40% reduction in exposure when co-administered with CARBO-ETOP or CIS-ETOP; administration of roniciclib had no effect on etoposide or platinum pharmacokinetics. The response rate was 81.4% (35/43) overall and 86.1% (31/36) in the pooled roniciclib 5 mg BID population (all partial responses). CONCLUSION: Roniciclib co-administered with chemotherapy in patients with ED-SCLC demonstrated tolerability, acceptable pharmacokinetics, and promising efficacy. An observed safety signal in a related phase II study resulted in discontinuation of the present study and termination of further roniciclib development.
OBJECTIVES: This phase Ib/II study evaluated safety, pharmacokinetics, maximum tolerated dose (MTD), and efficacy of the pan-cyclin-dependent kinase inhibitor roniciclib with cisplatin-etoposide (CIS-ETOP) or carboplatin-etoposide (CARBO-ETOP) in patients with extensive-disease small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS: In this open-label, non-randomized study, patients with previously untreated ED-SCLC received roniciclib twice daily (BID) in a 3 days on/4 days off schedule. Cisplatin 75 mg/m2 or carboplatin (AUC5) dose was administered on day 1, and etoposide 100 mg/m2 on days 1-3, of 21-day cycles. Phase Ib used a dose-escalation design to define the MTD for phase II. Pharmacokinetics were assessed. RESULTS: Forty-three patients received treatment (roniciclib 2.5 mg BID [+ CARBO-ETOP, n = 4; + CIS-ETOP, n = 3] and roniciclib 5 mg BID [+ CARBO-ETOP, n = 24; + CIS-ETOP, n = 12]). The MTD of roniciclib was 5 mg BID with CARBO-ETOP or CIS-ETOP. Common adverse events were nausea (90.7%) and vomiting (69.8%). Roniciclib was readily absorbed following oral administration at the MTD (median tmax 0.5-1 h), with a 30-40% reduction in exposure when co-administered with CARBO-ETOP or CIS-ETOP; administration of roniciclib had no effect on etoposide or platinum pharmacokinetics. The response rate was 81.4% (35/43) overall and 86.1% (31/36) in the pooled roniciclib 5 mg BID population (all partial responses). CONCLUSION:Roniciclib co-administered with chemotherapy in patients with ED-SCLC demonstrated tolerability, acceptable pharmacokinetics, and promising efficacy. An observed safety signal in a related phase II study resulted in discontinuation of the present study and termination of further roniciclib development.